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Characterization of fibroblast growth factor 1 binding heparan sulfate domain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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1999 (English)In: Glycobiology, Vol. 9, no 7, 723-729 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
1999. Vol. 9, no 7, 723-729 p.
URN: urn:nbn:se:uu:diva-89527OAI: oai:DiVA.org:uu-89527DiVA: diva2:161074
Available from: 2001-11-16 Created: 2001-11-16 Last updated: 2011-06-28Bibliographically approved
In thesis
1. Decoding Heparan Sulfate
Open this publication in new window or tab >>Decoding Heparan Sulfate
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Heparan sulfate (HS) is a polysaccharide of glycosaminoglycan type composed of alternating hexuronic acid [either glucuronic acid (GlcA) or iduronic acid (IdoA)] and glucosamine (GlcN) units that can be sulfated in various positions. HS binds to a large number of proteins and these interactions promote many biological processes, including cell adhesion and growth factor signaling. This thesis deals with the structural analysis of short heparan sulfate sequences that mediate binding to fibroblast growth factors FGF1 and FGF2, their receptor FGFR4, and the angiogenesis inhibitor endostatin.

Both FGF1 and FGF2 were shown to interact with N-sulfated hexa- and octasaccharide fragments isolated from HS. A pool of HS fragments depleted for FGF1 binding retained the ability to bind FGF2. Changes in 6-O sulfation affected binding to FGF1 but not FGF2, indicating that these proteins bind to distinct HS sequences.

All octasaccharides with high affinity for FGF1 contained an internal IdoA2S-GlcNS6S-IdoA2S trisaccharide motif as shown by exoenzyme-based sequence analysis. FGF2 bound to a mono-O-sulfated hexasaccharide with an internal IdoA2S unit, although the affinity was higher for a di-O-sulfated octasaccharide displaying an IdoA2S-GlcNS-IdoA2S trisaccharide motif.

FGFR4 was shown to bind the HS analogue heparin with a KD value of 0.3 μM.

The interaction between FGFR4 and HS depends on both IdoA2S and GlcNS6S units. Sequence analysis suggested that the number but not the precise location of 6-O-sulfate groups determines affinity.

The HS-binding site of endostatin was identified through alanine scanning. Endostatin mutants with reduced affinity for HS were unable to counteract angiogenesis induced by FGF2. The predominant HS motif recognized by endostatin was shown to consist of two N-sulfated domains separated by N-acetylglucosamine units.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2001. 46 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1098
Biochemistry, Heparan sulfate, fibroblast growth factor, receptor, endostatin, angiogenesis, interaction, sequence, Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
urn:nbn:se:uu:diva-1499 (URN)91-554-5161-6 (ISBN)
Public defence
2001-12-07, lecture hall C10:305, Uppsala Biomedical Center, Uppsala, 09:15
Available from: 2001-11-16 Created: 2001-11-16Bibliographically approved

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Kreuger, Johan
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